Saturday, 31 October 2015

Bad B cells make GM-CSF

Li et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy.Sci Transl Med. 2015 Oct 21;7:310ra166.

Background: B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a pro-inflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases.

Immunology is complex and gets more complex as more discoveries occur. We know that the B cell is where the action is. With the exception of daclizumab all highly effective DMTs have an effect on B cells. The fact that targeting mainly B cells with anti-CD20 therapy has proven to be very effective is proof that the B cell is likely to be the main target of these therapies.  This is associated with the loss of B cell population that makes a cytkine called GM-CSF which controls a B regulatory cell that produces interleukin 10. So we have pathogenic and regulatory B cells will they replace pathogenic and regulatory B cells

4 comments:

  1. Very frustrating that the MS societies and pharmaceutical companies still beat to the beat of the T cell drum. I can't believe that for almost a decade now, anti b cell therapies like rituximab and alemtuzumab that have been very effective, have been ignored and glanced over. How did this momentum that it was primarily a T cell activated autoimmune disease get started? Tysabri and Gilenya, both of which primarily target T cell infiltration past the BBB, are ineffective in progressive MS. I believe that these therapies will only reduce relapses caused by active inflammation, but by not addressing b cells early on, progression will occur with virtually all MS patients, including RRMS. HSCTs effectiveness lies in its efficient elimination of b cells, not all though, trapped behind the CNS. I think that there needs to be a paradigm shift in the autoimmune mechanism and pathophysiology of MS that includes b cells/plasma cells present chronically. It's why HSCT may only have a "life span" of ten to fifteen years. Lastly, MS may need to be treated over a lifetime with such anti-b cell therapies. Just my two cents. I was treated in Florence Italy last year for late RRMS/early SPMS (unknown) and am hoping for maybe a decade of remission. But I do plan on going on ocrelizumab when available in a year's time.

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    1. Alpha-4 integrin is also expressed on B cells, possibly at higher levels than on T cells (see here: http://fournierlab.mcgill.ca/resources/Pubs_PDFs/2006-Ann-Neurol.pdf). Natalizumab decreases B cell counts in CSF (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677530/). It decreases antibody production in CSF and eliminates oligoclonal bands in some patients (http://www.ncbi.nlm.nih.gov/pubmed/23093485).

      So where is the claim that natalizumab is T cell treatment coming from? Did you just make it up?

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    2. I agree it is a B cell agent as well as an anti-T cell and anti-monocyte agent.

      Where did the idea of natalizumab being a T cell agent...I think you will find it is californian, south of San fransisco

      Stanford to be precise. Thats why is was discovered

      Although the line used to find that anti-CD49d inhibited adhesion was I think U937 histocytic lymphoma which is used to study monocyte function.

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  2. From the method of action on the natalizumab wiki:

    The symptom-causing lesions of MS are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood–brain barrier ...

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